Promoter hypermethylation is not the major mechanism for inactivation of the FBXW7 beta-form in human gliomas.
FBXW7 has been reported to be a candidate tumor suppressor gene on 4q31. Three isoforms (alpha-form, beta-form, and gamma-form) of FBXW7 are produced from mRNAs with distinct 5' exons. Our previous study identified the specific suppression of the mRNA expression of the FBXW7 beta-form in human gliomas. Because this form is the major FBXW7 isoform in the human brain, we elucidated the silencing mechanisms for the FBXW7 beta-form in gliomas. No genetic alterations were found in the whole FBXW7 gene including putative promoter region of the beta-form. Treatments with 5-azacytidine and trichostatin A did not induce re-expression. A sodium bisulfite-modification assay indicated that CpG sequences in the promoter of FBXW7 beta-form were not methylated in glioma cells. Meanwhile we searched for the expression of FBXW7 and the sodium bisulfite sequences in normal human peripheral blood cells, and we surprisingly found that the mRNA expression of the FBXW7 beta-form was highly suppressed and the CpG sequences in the promoter region of the FBXW7 beta-form were heavily methylated. Our data suggest that the inactivation of the FBXW7 beta-form plays an important role in the pathogenesis of gliomas and that an unknown mechanism(s) other than mutation and methylation is the major cause of the suppression of the FBXW7 beta-form in gliomas.
Gu
Zhaodi
Z
Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Japan.
Inomata
Kenichi
K
Mitsui
Hidetoshi
H
Horii
Akira
A
D001374:Azacitidine / Q000494:pharmacology; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000502:physiology; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D006877:Hydroxamic Acids; D007527:Isoenzymes; C012589:trichostatin A; D044767:Ubiquitin-Protein Ligases; D001374:Azacitidine